Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.
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人类2型糖尿病胰岛中PPARGC1A的表观遗传调节以及对胰岛素分泌的影响。
DOI：
10.1007/s00125-007-0916-5
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发表时间：
2008-04
期刊：
影响因子：
8.2
通讯作者：
Del Prato, S.
中科院分区：
文献类型：
--
作者：
Ling, C.;Del Guerra, S.;Lupi, R.;Ronn, T.;Granhall, C.;Luthman, H.;Masiello, P.;Marchetti, P.;Groop, L.;Del Prato, S.
关键词：
胰岛中的胰岛素分泌依赖于线粒体功能和ATP的产生。转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子-1 α（蛋白质PGC-1α;基因PPARGC 1A）是线粒体基因的主要调节因子，其表达降低，与2型糖尿病患者肌肉中氧化磷酸化受损相关。它是否在人类胰岛中发挥类似的作用尚不清楚。因此，我们研究了2型糖尿病患者胰岛中PPARGC 1A表达是否改变，以及这种表达是否受遗传（PPARGC 1A Gly 482 Ser多态性）和表观遗传（DNA甲基化）因素的影响。我们还测试了在人类胰岛中PPARGC 1A表达的实验性下调是否影响胰岛素分泌。PPARGC 1A Gly 482 Ser多态性在48例非糖尿病和12例2型糖尿病多器官供体的人胰岛中进行基因分型，并与PPARGC 1A mRNA表达相关。分析了10例2型糖尿病患者和9例对照供体胰岛中PPARGC 1A启动子的DNA甲基化。用PPARGC 1A沉默RNA（siRNA）转染分离的人胰岛。PPARGC 1A mRNA表达降低了90%（p < 0.005），并且与2型糖尿病患者胰岛中胰岛素分泌的减少相关。在通过siRNA下调人胰岛中PPARGC 1A表达后，胰岛素分泌减少了41%（p ≤ 0. 05）。01）。我们能够将胰岛中PPARGC 1A表达的降低归因于遗传和表观遗传因素，即共同的PPARGC 1A Gly 482 Ser多态性与PPARGC 1A mRNA表达的降低（p < 0.00005）和胰岛素分泌的降低（p < 0.05）相关。为了支持表观遗传影响，PPARGC 1A基因启动子显示糖尿病胰岛中的DNA甲基化比非糖尿病胰岛增加两倍（p < 0.04）。我们首次发现PPARGC 1A在人胰岛胰岛素分泌中可能是重要的，并且PPARGC 1A在人胰岛中的表达可以受到遗传和表观遗传因素的调节。
Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1α; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion. The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA). PPARGC1A mRNA expression was reduced by 90% (p < 0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p ≤ 0. 01). We were able to ascribe reduced PPARGC1A expression in islets to both genetic and epigenetic factors, i.e. a common PPARGC1A Gly482Ser polymorphism was associated with reduced PPARGC1A mRNA expression (p < 0.00005) and reduced insulin secretion (p < 0.05). In support of an epigenetic influence, the PPARGC1A gene promoter showed a twofold increase in DNA methylation in diabetic islets compared with non-diabetic islets (p < 0.04). We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors.
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DOI：
10.1073/pnas.1032913100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Patti, ME;Butte, AJ;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
3.5
作者：
Fakhrai-Rad, H;Nikoshkov, A;Galli, J
通讯作者：
Galli, J
影响因子：
7.7
作者：
Muller, YL;Bogardus, C;Baier, L
通讯作者：
Baier, L
影响因子：
11.8
作者：
Yoon, JC;Xu, G;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
7.7
作者：
Masiello, P;Broca, C;Ribes, G
通讯作者：
Ribes, G